One of the most common comorbid pathology is asthma and arterial hypertension. For experimental modeling of comorbidity we have used spontaneously hypertensive rats with ovalbumin (OVA)-induced asthma. Rats were randomly divided into three groups: control group, OVA-induced asthma group; OVA-induced asthma + IL10 shRNA interference group. Target gene (IL10) was predicted by ANDSystem. We have demonstrated that RNA-interference of IL10 affected cardiovascular (tested using Millar microcatheter system) as well as respiratory functions (tested using force-oscillation technique, Flexivent) in rats. We have shown that during RNA-interference of IL10 gene in vivo there were changes in both cardiac and lung function parameters. These changes in the cardiovascular parameters can be described as positive. But the more intensive heart workload can lead to exhaust and decompensation of the heart functions. Knockdown of IL10 gene in asthma modeling induces some positive changes in respiratory functions of asthmatic animals such as decreased elastance and increased compliance of the lungs, as well as less pronounced pathomorphological changes in the lung tissue. Thus, we provide the data about experimentally confirmed functionality changes of the target which was in silico predicted to be associated with both asthma and hypertension – in our new experimental model of comorbid pathology.

Aims Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation in diabetic mice (db/db) to alleviate endothelial and vascular dysfunction. Methods and Results Left-internal mammary arteries from patients undergoing coronary artery bypass grafting (CABG) with or without a diagnosis of diabetes were assayed for SIRT1 protein levels. Twelve-week-old male db/db mice and db/+ controls were treated with vehicle or rmSIRT1 i.p. for 4 weeks, after which carotid artery pulse wave velocity (PWV) and energy expenditure/activity were assessed by ultrasound and metabolic cages, respectively. Aorta, carotid, and mesenteric arteries were isolated to determine endothelial and vascular function using myograph system. Arteries obtained from diabetic patients had significantly lower levels of SIRT1 than non-diabetic controls. Likewise, aortic SIRT1 levels were reduced in db/db mice compared to db/+ mice, while rmSIRT1 supplementation restored it to levels of controls. Mice treated with rmSIRT1 displayed increased physical activity and improved vascular compliance as reflected by reduced PWV and attenuated collagen deposition. Aorta of rmSIRT1-treated mice exhibited increased endothelial nitric oxide (eNOS) activity, and endothelium-dependent contractions of their carotid arteries were significantly decreased, while mesenteric resistance arteries showed preserved hyperpolarization. Ex-vivo incubation with reactive oxygen species scavenger (ROS) Tiron and NADPH oxidase inhibitor apocynin revealed that rmSIRT1 preserved vascular function by supressing NADPH oxidase (NOX)-related ROS sythesis. Chronic rmSIRT1 treatment suppressed the expression of NOX-1 and NOX-4, in line with a reduction in aortic protein carbonylation and plasma nitrotyrosine levels. Conclusions In diabetic conditions, arterial SIRT1 is reduced. Chronic rmSIRT1 supplementation improves endothelial function and vascular compliance by enhancing eNOS activity and suppresses NOX-related oxidative stress. Thus, SIRT1 supplementation may be a novel therapeutic strategy preventing diabetic vascular disease. Translational perspective The growing burden of obesity and diabetes drives an increasing portion of atherosclerotic cardiovascular disease, and represents a major challenge to public health. Herein, we probe the efficacy of recombinant SIRT1 supplementation to preserve endothelial function and vascular compliance during diabetic conditions. Notably, SIRT1 levels were diminished in diabetic arteries of mice and humans alike, while recombinant SIRT1 delivery improved energy metabolism and vascular function by suppressing oxidative stress. Our study deepens mechanistic insights into the vasculo-protective effects conferred by recombinant SIRT1 supplementation and opens therapeutic avenues to mitigate vascular disease in diabetic patients.

The level of expression of miR-196a in patients with chronic viral hepatitis C with the first genotype of HCV according to previous experience of antiviral therapy. Shostakovych-Koretskaya L.R., Shevchenko-Makarenko O.P., Lapikova-Bryhinska T.Yu. The authors present the study of the level of expression of miR-196a in 74 patients with chronic viral hepatitis C with the 1st genotype of HCV, based on previous experience in patients with antiviral therapy regimens containing interferon. The patients were divided into two groups, depending on the previous experience of antiviral therapy with circuits containing interferon -21 patients who failed after antiviral therapy regimens containing interferon (group 1) and the comparison group (group 2) -53 naive patients. To study the level of expression of miR-196a (miR-196a), a two-stage study according to the manufacturer's protocol was used. First, total RNA was isolated from the plasma by the method of phenol-chloroform extraction. Futher reverse transcription was performed using a kit for reverse transcription of miR TaqMan® (Applied Biosystems, USA), specific loop primers to achieve mature miRNA, snRNA U6 (as an endogenous control gene), and 10 ng of total RNA. Real-time quantitative PCR was performed using TaqMan® miRNA analysis. In order to optimize the prediction of response to antiviral therapy and the use of optimal treatment regimens for problem patients with treatment failure regimens containing interferon, analysis using ROC curves was used. The average level of expression of miR-196a in patients with chronic hepatitis C was evaluated. In the 1st group of patients it was 0.011 (IQR: 0.002; 0.310) and in the comparison group -0.346 (IQR: 0.054; 1.239) at p=0.012 by U criterion. The conducted ROC analysis showed that the studied miR-196a could differentiate patients with chronic viral hepatitis C with HCV genotype 1, depending on previous experience of antiviral therapy, namely, patients with treatment failure regimens containing interferons and naive. AUC=0.688 (95% CI 0.570-0.791; p=0.017), J=0.40, Se=57.14%, Sp=83.02%. It gives additional opportunities for correction of therapeutic tactics. Therefore, the level of expression of miR-196a (<-1,75) may be an additional biomarker in the pathogenesis of HCV-infection, which can then be used in the monitoring and treatment of patients. Low expression of miR-196a may be the basis for prescribing more effective direct-acting antiviral therapy to patients and will allow personalizing therapeutic tactics in patients with chronic viral hepatitis C.Реферат. Рівень експресії мікроРНК-196a у хворих на хронічний вірусний гепатит С з першим генотипом HCV, залежно від попереднього досвіду противірусної терапії. Шостакович-Корецька Л.Р., Шевченко-Макаренко О.П., Лапикова-Бригинська Т.Ю. Авторами представлено вивчення рівня експресії мікроРНК-196a у 74 хворих на хронічний вірусний гепатит С з 1-м генотипом HCV. Хворих було розподілено на дві групи залежно від попереднього досвіду противірусної терапії схемами, що містять інтерфер...

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